メチルグリオキサール解毒障害による統合失調症様行動異常発現の分子機序解明

抄録

Methylglyoxal (MG) is a reactive and cytotoxic alpha-dicarbonyl product of glycolysis. Various detoxification systems work together in vivo to remove highly toxic MGs, including a glyoxalase system by Glyoxalase 1 (GLO1) and GLO2, and the scavenging system by vitamin B6 (VB6). We found that VB6 levels in peripheral blood of the schizophrenia patients with GLO1 dysfunction are significantly lower than that of healthy controls. However, the effects of the MG detoxification deficits on the pathophysiology of schizophrenia remains poorly understood. Here, we generated a new mouse model of schizophrenia with impaired MG detoxification by feeding Glo1 knockout mice VB6-deficent diets (KO/VB6(-)). KO/VB6(-) mice accumulated MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed behavioral deficits, such as prepulse inhibition (PPI) deficit. Furthermore, we demonstrated abnormal mitochondrial respiratory function and subsequently enhanced oxidative stress in the PFC of KO/VB6(-) mice in the PFC. Finally, administration of an antioxidant resveratrol improved PPI impairment as well as oxidative stress. These results suggest that the combination of GLO1 dysfunction and VB6 deficiency results in mitochondrial dysfunction and increased oxidative stress in PFC, resulting in schizophrenia-like behavioral disorders.